BACKGROUND: Saccharomyces cerevisiae is a common environmental fungus and an uncommon, but increasingly recognized, cause of invasive fungal infection. The clinical manifestations of this infection can often be mistaken for histoplasmosis, a major cause of mortality in patients with advanced HIV. OBJECTIVES: To review the current epidemiology, diagnostic approaches, and management strategies for S. cerevisiae infection in patients with HIV. SOURCES: A literature search was conducted using PubMed from January 1980 and May 2024. CONTENT: This review features a case of S. cerevisiae infection in a patient with HIV to highlight the diagnostic challenges and clinical implications of disseminated infection. A summary of published cases in patients with vs. without HIV is provided alongside a review and discussion of both conventional and novel diagnostic methods. The role of current antifungal therapies in managing S. cerevisiae infections is also examined. IMPLICATIONS: S. cerevisiae is a rare but clinically important opportunistic pathogen in patients with advanced HIV who have epidemiologic risk factors. When found in mucocutaneous lesions under the appropriate clinical scenario, S. cerevisiae should not automatically be dismissed as commensal flora.